Genistein and daidzein are estrogenic isoflavones found in soybeans. Although they are about 1/10,000 as potent as estradiol, infants fed soy formula have serum concentrations that are up to 4 orders of magnitude higher than estradiol. Clinical trial data show increases in cholesterol synthesis consistent with an estrogen effect in infants fed soy formula vs. human milk or cow milk formula, and lowered response to polio vaccination, which might or might not be an estrogen effect. Anatomic, sonographic, and other biochemical evidence of estrogen exposure has not been looked for in infants fed soy. Whether such widely used products do or do not have clinically detectable estrogenic activity in infants, the group with the highest exposure per kilo, is important clinically; in addition, it may be a crucial test of the ability of laboratory measures of estrogenicity to predict actual endocrine response in humans. We have begun pilot studies to examine the natural history of estrogen responsive physiology in the newborn, and will use the results to develop a longitudinal study of the possible estrogenic effects of soy formula on infants. At the Boston Children?s Hospital, our collaborators in pediatric ultrasound have developed and assessed inter- and intra- rater reliability for examinations of the breast, uterus, ovaries, testes, prostate, adrenals, and thyroid. Using a protocol and eligibility criteria developed at NIEHS, by fall 2004 they will have examined 96 girls, ranging in age from less than 48 hours to one year, and 60 boys, ranging in age from less than 48 hours to 6 months. About one third of the children were soy fed, one third breast fed, and one third cow milk formula fed. This pilot data will allow us to see whether the methods are reliable and show variability, but there are not enough children for testing hypotheses about soy vs the other feeding methods. At the Children's Hospital in Philadelphia, our collaborators are doing physical examinations of the breasts and genitalia of 84 children total of both sexes ages from less than 48 hours to 6 months. This examination is a modification of the well-known Ballard scale for gestational age, which uses the degree of estrogen response by the breasts and genitals. The degree of estrogenization is so strongly related to gestational age that the weeks in utero for the child can be estimated using this examination. We are using it in children as they get older and the effects of maternal estrogen wane. As with the ultrasounds, the idea is to show inter- and intra-rater reliability, variability, and feasibility. There are not enough children to test hypotheses. We are also collecting samples at this site for analysis of isoflavones (at CDC and FDA) and a variety of hormones (at NICHD). We hope to have the physical examination, ultrasound, and isoflavone data by winter of 2004-5, and begin planning the next study.